Comparative acute oral toxicity of sodium warfarin and microcrystalline warfarin in the Sprague-Dawley rat

Abstract

Summary The acute oral toxicities of sodium warfarin and a microcrystalline form of acid (enol) warfarin (MICROFARIN) were compared in male and female Sprague-Dawley rats. The drugs were administered in carboxymethylcellulose by gastric needle, and the rats were observed for a 14-day period. The LD 50 , calculated on the basis of probit-log plots and formulae, according to Bliss, for sodium warfarin was 100.3 ± 1.5 mg/kg (0.3037 mmol/kg) for male rats and 8.7 ± 1.2 mg/kg (0.0263 mmol/kg) for female rats. The LD 50 for microcrystalline warfarin for male rats was 112 ± 1.6 mg/kg (0.363 mmol/kg) and 10.4 ± 1.1 mg/kg (0.00337 mmol/kg) for female rats. Both warfarin preparations exhibited the same range of toxicity; the toxicity for both drugs was approximately 10 times greater in the female than in the male rat. Except for the highest dose of warfarin preparations studied (320 mg/kg), the period of highest mortality was between the 4th and 10th post-treatment day. Autopsy revealed hemorrhages into the intestine, thoracic cavity, peritoneal cavity, and urinary bladder. The data show that the microcrystalline form of warfarin is absorbed from the gastrointestinal tract and that its LD 50 is similar to that of sodium warfarin.